Trans Cranial Direct Current Stimulation

1. TRANSCRANIAL
DIRECT CURRENT
STIMULATION
(TDCS)*
*FOR CL PSYCHIATRISTS
DAVIN QUINN, MD
NOVEMBER 13, 2014
APM ANNUAL MEETING, FORT LAUDERDALE, FL

2. DISCLOSURES
None

3. OUTLINE
What CL Psychiatrists Need to Know
Complications of tDCS
Efficacy of tDCS
Indications/Contraindications for tDCS
Mechanism of Action of tDCS
What is tDCS?
Brief History of Electrical Stimulation

4. BRIEF HISTORY OF
ELECTRICAL STIMULATION
SECTION 1

5. EARLY BRAIN STIMULATION
Ancient civilizations applied the
electric torpedo fish to the head
to treat illness (Kellaway 1946)
Kellaway P. The part played by electric fish in the early history of
bioelectricity and electrotherapy. Bull Hist Med 1946; 20(2): 112-137.

6. 18-19TH CENTURIES
Giovanni Aldini in 1803 used
voltaic devices to stimulate
patients and corpses (Aldini 1803)
Rudolph Arndt in 1870 applied
electrotherapy to the scalp to treat
mental illness (Steinberg 2013)
Stagg CJ, Nitsche MA. Physiological basis of tDCS. Neuroscientist 2012. Steinberg H. A pioneer work on electric brain stimulation in psychotic patients: Rudolph Gottfried Arndt
and his 1870s studies. Brain Stim 2013; 6: 477-481.

7. 20TH CENTURY
“Electrosleep
Therapy” (1950s)
• Russian experiments
“Brain Polarization”
(1970s)
• British, US experiments
“tDCS” (2000)
• Nitsche, Paulus Clark VP, Parasuraman R. Neuroenhancement: enhancing brain and
mind in health and disease. Neuroimage 2014; 85: 889-894.

8. WHAT IS TDCS?
SECTION 2

9. WHAT IS TDCS?
A form of brain stimulation:
• Non-invasive
• Non-focal
• Non-convulsive
Delivers low currents of electricity
• Patient is conscious
• Minimal discomfort
Modulates spontaneous neuronal activity
• Neurons become more or less likely to fire
• Does not trigger action potentials
• More charge over time ~ longer lasting effect

10. DIRECT CURRENT
The electrode placement and
direction of current flow has
specific effects (George 2010)
Anodal current = depolarizing
Cathodal current = hyperpolarizing
George MS, Aston-Jones G. Noninvasive techniques for probing neurocircuitry and treating illness: VNS, TMS, and tDCS. Neuropsychopharmacology 2010; 35: 301-316. Saote C,
Turi Z, Paulus W, Antal A. Combining functional magnetic resonance imaging with tDCS. Front Hum Neurosci 2013; 7 (435): 1-7.

11. TDCS APPLICATION
Clark VP, personal communication, 2014

12. CONSTANT CURRENT
tDCS is not pulsatile, so there
is no pulsewidth variable.
Voltage varies to maintain
current constant (V = IR)
Current strength is varied
depending on desired intensity
of stimulation.
Current duration is varied
depending on desired total
charge.
Nitsche MA et al. TDCS: state of the art 2008. Brain Stimulation 2008;
1: 206-223.

13. MECHANISM OF ACTION OF
TDCS
SECTION 3

14. ANIMAL STUDIES
Applied cortical direct currents
resulted in long-lasting
changes in firing rates (Bindman
1963)
Changes in firing rates
dependent on protein
synthesis, calcium handling,
cAMP accumulation (Gartside
1968, Nitsche 2008)
Bindman LJ, LIppold OCJ, Redfearn JWT. Long-lasting changes in the level of the electrical activity of the cerebral cortex produced by polarizing currents. Nature 1962; 4854: 584-
585. Gartside IB. Mechanisms of sustained increases of firing rate of neurones in the rat cerebral cortex after polarization: role of protein synthesis. Nature 1968; 220: 383-384.

15. POLARIZING CURRENT
Electric fields penetrate the
scalp and cause polarization of
neurons, increasing or
decreasing their excitability (de
Berker 2013)
de Berker AO, Bikson M, Bestmann S. Prediciting the behavioral impact of transcranial direct current stimulation: issues and limitations. Front Hum Neurosci 2013; 7(613): 1-6.
Miranda PC, Lomarev M, Hallett M. Modeling the current distribution during tDCS. Clin Neurophys 2006; 117: 1623-1629. de. Pazzarini M, Fiocchi S, Rossi E, Paglialonga A,
Ravazzani P. tDCS: estimation of the electric field and of the current density in an anatomical human head model. IEEE transactions on biomedical engineering 2011; 58(6): 1773-
1780.

16. TDCS MODULATES CORTICAL
EXCITABILITY
Priori A. Brain polarization in humans: a reappraisal of an old tool for prolonged non-
invasive modulation of brain excitability. Clin Neurophys 2003; 114: 589-595.
Wassermann EM, Grafman J. Recharging cognition with DC brain polarization.
Trends Cog Sci 2005; 9(11): 503-505. Nitsche MA, Paulus W. Excitability changes
induced in the human motor cortex by weak transcranial direct current stimulation. J
Physiol 2000; 527(3): 633-639.
Motor evoked potentials are
facilitated by anodal tDCS and
inhibited by cathodal (Nitsche 2000)

17. TDCS INDUCES LTP-LIKE
NEUROPLASTICITY
LTP is a persistent increase in
neuronal transmission after
synchronous stimulation.
tDCS-induced changes in
neuronal firing are dependent
on NMDA, Ca++, and BDNF like
LTP
Monte-Silva K, Kuo MF, Hessenthaler S, Fresnoza S, Liebetanz D, Paulus W, Nitsche MA. Induction of late LTP-like plasticity in the human motor cortex by repeated non-
invasive brain stimulation. Brain Stim 2013; 6: 424-432. Fritsch B, Reis J, Martinowich K, Schambra HM, Ji YY, Cohen LG, Lu B. Direct current stimulation promotes BDNF-
dependent synaptic plasticity: potential implications for motor learning. Neuron 2010; 66: 198-204.

18. TDCS FOCAL EFFECTS
N-acetyl aspartate increased
focally under the electrode (Clark
2011)
Cerebral blood flow increases
under the electrode (Lang 2005)
Clark VP, Coffman BA, Trumbo MC, Gasparovic C. TDCS produces localized and specific alterations in
neurochemistry: a 1H MRS study. Neurosci Lett 2011500: 67-71. Lang N, Siebner HR, Ward NS, Lee L, Nitsche MA,
Paulus W, Rothwell JC, Lemon RN, Frackowiak RS. How does TDCS of the primary motor cortex alter regional
neuronal activity in the human brain? Eur J Neurosci 2005; 22: 495-504. Jang SH, Ahn SH, Byun WM, Kim CS, Lee
MY, Kwon YH. The effect of TDCS on the cortical activation by motor task in the human brain: an fMRI study.
Neurosci Lett 2009; 460: 117-120.

19. TDCS NONFOCAL
tDCS effects are diffuse
and spread over
multiple regions and
networks. (Lang 2005)
Lang N, Siebner HR, Ward NS, Lee L, Nitsche MA, Paulus W, Rothwell JC, Lemon RN, Frackowiak RS. How does tDCS of the primary motor cortex alter regional
neuronal activity in the human brain? Eur J Neurosci 2005; 22: 495-504. Pena-Gomez C, Sala-Lonch R, Junque C, Clemente IC, Vidal D, Bargallo N, Falcon C, Valls-
Sole J, Pascual-Leone A, Bartres-Faz D. Modulation of large-scale brain networks by tdcs evidenced by resting-state fMRI. Brain Stim 2012; 5: 52-63.

20. INDICATIONS/CONTRAINDI
CATIONS FOR TDCS
SECTION 4

21. DC STIMULATORS
Not FDA Approved for use
in Psychiatric Disorders
• Certain devices are FDA
approved for iontophoresis
Studied in:
• Stroke rehabilitation
• Memory/Alzheimers
• Depression/Emotion
• Learning/Perception
• Pain/Fibromyalgia
• Addiction/Impulsivity
• Tinnitus
• Epilepsy
Exclusions from
studies:
• Metal implant
• Pregnancy
• Seizure disorder
• Ongoing substance use

22. EFFICACY OF TDCS IN
DEPRESSION, STROKE,
COGNITION
SECTION 5

23. TDCS FOR STROKE
Hummel F, Celnick P, Giraux P, Floel A, Wu WH, Gerloff C, Cohen LG. Effects of non-invasive cortical stimulation on
skilled motor function in chronic stroke. Brain 2005; 128: 490-499.Adeyemo BO, Simis M, Macea DD, Fregni F.
Systematic review of parameters of stimulation, clinical trial design characteristics, and motor coutcomes in non-
invasive brain stimulation in stroke. Front Psychiatry 2012; 3 (88): 1-27.

24. DEPRESSION
120 mod-severe nonpsychotic
MDD pts received sertraline 50
mg daily (60) or placebo (60)
(Brunoni 2013)
60: 12 tx tDCS: 2 mA DLPFC (L
anodal/R cathodal) x 30min
60: sham tDCS
Brunoni AR, Valiengo L, Baccaro A, Tamires AZ, Oliveira JF, Goulart A, Boggio PS, Lotufo PA, Bensenor IM, Fregni F. The sertraline versus electrical current therapy for treating
depression study clinical study. JAMA Psychiatry 2013; 70(4): 383-391.

25. LEARNING
fMRI of detection task in 96 pts
revealed R Frontal and Parietal
foci of activation (Clark 2012)
Anodal 2 mA tDCS x 30 min to
these areas led to faster
learning
Clark VP, Coffman BA, Mayer AR, Weisend MP, Lane TDR, Calhoun VD, Raybourn EM, Garcia C, Wasserman EM. tDCS guided using fMRI significantly accelerates learning to identify
concealed objects. Neuroimage 2012; 59: 117-128.

26. LEARNING
Clark VP, Coffman BA, Mayer AR, Weisend MP, Lane TDR, Calhoun VD, Raybourn EM, Garcia C, Wasserman EM. tDCS guided using fMRI significantly accelerates learning to
identify concealed objects. Neuroimage 2012; 59: 117-128.

27. TDCS FOR MMTBI
US: 1.7 million TBIs annually
NM 2nd among 34 states in TBI deaths
Suicide by firearm (38%)
Motor vehicle accident (22%)
Falls (17%)
Homicide (12%)
NM Brain Injury Advisory Council, www.nmbiac.com.
Traumatic Brain Injury in the United States,
www.cdc.gov/TraumaticBrainInjury Yeo RA, personal correspondence

28. COMPLICATIONS OF TDCS
SECTION 6

29. SIDE EFFECTS
Hypomania/Insomnia
Drowsiness/Fatigue
Skin Itching/Burning
Nausea/Headache
NO seizures
NO autonomic/CV effects
NO lasting cognitive changes
**Both utilized Neuroconn devices
Palm U, Keeser D, Schiller C, Fintescu Z, Reisinger E, Nitsche M, Padberg
F. Skin lesions after treatment with tDCS. Brain Stim 2008; 1: 386-387.
Frank Em Wilfurth S, Landgrebe M, Eichhammer P, Hajak G, Langguth B.
Anodal skin lesions after treatment with tDCS. Brain Stim 2010; 3: 58-59.
Arul-Anandam AP, Loo C, Mitchell P. Induction of hypomanic episode with
tDCS. J ECT 2010; 26)7): 68-69. Vandermeeren Y, Jamart J, Ossemann M.
Effect of tDCS with an extracephalic reference electrode on cardio-
respiratory and autonomic functions. BMC Neurosci 2010; 11: 38. Poreisz C,
Boros K, Antal A, Paulus W. Safety aspects of TDCS concerning healthy
subjects and patients. Brain Res Bull 2007; 72: 208-214.

30. WHAT CL PSYCHIATRISTS
NEED TO KNOW
SECTION 7

31. NEED TO KNOW
TDCS is:
• Extremely safe
• Induces neuroplasticity and
modulates neuronal activity both
focally and nonfocally
• Not FDA approved for use on the
brain
• Potentially synergistic with
medications
• Likely to cause mild side effects
• Most likely to affect your current
practice—when video gamer comes
into the ED with scalp burns from
DIY TDCS
• A potential therapy for many
psychosomatic medicine disorders
http://smartdrugsmarts.com/do-it-yourself-transcranial-direct-current-
stimulation/

32. THANKS
UNM Center for Brain
Recovery and Repair
Bill Shuttleworth
Ronald Yeo
Richard
Campbell
UNM Psychology
Clinical
Neuroscience Center
Vince Clark
Brian Coffman
UNM Department of
Psychiatry
Mauricio Tohen
Chris Abbott
Alya Reeve
Brant Hager
MIND Research
Network
Andrew Mayer
Stefan Klimaj

33. Murat Altinay, MD |
Fellow in Mood Disorders and Neurosciences
Cleveland Clinic Foundation
Department of Psychiatry

34.  None.

35. Introduction
VNS 1.0.1
(Vagus nerve
anatomy and
VNS basics)
History
Research
Studies
Clinical
Use
Safety/
Compli
ance

36.  Major depressive disorder (MDD):
 Common
 Recurrent
 Chronic
 Leading contributor to disability
 Current treatments fall short (~20 to 40% failing to
respond to AD trials)
 Psychotropic medications,
 Psychotherapy,
 ECT
 STAR-D highlighted these limitations.
 Failure of depression to respond to currently available
treatment options-- major treatment challenge.

38.  VNS is an implantable neuromodulation device which
has established efficacy in pharmaco-resistant
epilepsy.
 July 2005:
 FDA approval as an adjunctive treatment of severe,
recurrent unipolar and bipolar depression.
 Other disorders (under investigation):
 Anxiety,
 Migraines
 Alzheimer’s disease.

39. Innervation
- larynx,
- esophagus,
- trachea,
- heart,
- aorta, and GI
The right
vagus:
HR regulation
 SA node
(pace maker
of the heart)
The left
vagus:
AV node (less-
no influence in
HR)

40. NTS
(bilaterally)
Left
Vagus
nerve
PAG
Limbic
regions
Locus
Cereleus
Raphe
Nuclei
Cortex
PBNhypothalamu
s, thalamus,
amygdala,
and nucleus
of the stria
terminalis.
Thalamus 
insular,
orbitofrontal,
and
prefrontal
cortices,
NE, 5HT
Projections

41.  The VNS device:
 generator  electrodes 
low-frequency, chronic
intermittent-pulsed electrical
signals  left cervical vagus
nerve.
 Separate incision in the neck
 stimulating electrodes
wrapped around the left
cervical vagus nerve.
 Subcuteanous tunelling
procedure
 Electrodes are connected to
the implanted generator.

43.  VNS was approved for pharmaco-resistant epilepsy in
Europe in 1994 and in the US in 1997.
 Anecdotal clinical observations of mood improvement
in epilepsy patients after VNS implantation.
 Role for VNS therapy in depression??
July 2005:
FDA approval as an adjunctive treatment of severe,
recurrent unipolar and bipolar depression.

44.  Epilepsy Studies
 Harden et al. (2000)
 A pilot prospective study
 VNS effects on mood in epilepsy patients
 VNS device vs. anti-epileptic drugs
 Significant mood improvement in the VNS group at 3 months.
(HAMD, HAMA, BDI, CDRS)
 Elger et al. (2000)
 11 epilepsy pts w/ mild MDD.
 Baseline
 9 /11 subjects had significant depressive symptoms
 Only 2/10 at 6-months follow up.
 Only 2/11 subjects in the trial could be classified as responders in terms of
seizure reduction over the 6-months
 These findings suggested that VNS has a separate and distinct
effect on depressive symptoms not related to outcomes on
seizures

46.  Open label Studies
• 30 pts with chronic uni/bipolar depression
who had failed ≥ 2 AD trials.
• Implantation 2 week recovery (no
stim) 10 weeks of stim + existing fixed
med.
• Results: Response rate of 40% and a
remission rate of 17%.
Rush et al
(2000)
• 30 TRD unipolar and bipolar patients for a
total sample size of 60.
• 12 weeks (2 week post-surgery w/o stim
10 weeks of VNS) to determine the acute
response to VNS.
• Response rate: 30% (HAM-D-28). 37%
CGI-I and 34% on the MADRS.
• Remission (HAM-D score <10) : 15%.
O’Reardon
et al

47.  Randomized Controlled studies
 Rush et al. (2005)
 A negative trial.
 Multi-center trial of VNS (n=225)
 Active vs. sham VNS
 10-weeks of active stimulation the response rate on HAM-D24
was 15% (n=112) and the sham/placebo response rate was 10%
(n=110), which did not differ from each other (p=0.238).
 BUT– well tolerated + better response rate on self report
measure IDS-SR-30.

48.  The first pilot study (Rush et al. 2000) followed patients
over 12 months:
 Response rates increase over time (HAMD24 response rate was
27.2% ; remission rate (HRSD(24) < or = 9) 15.8% )
 10-week trials of VNS might underestimate its potential
to treat TRD patients.
 Marangell et al. (2002)
 Additional 9-months of VNS (1 year total)
 Response rate slightly increased from 40  46%
 Remission rate increased 17% (3 months) to 29% at 1
year

49. 2 years
Results remained similar:
- response rate of 42% and
a - remission rate of 22%
- Overall response
rate : 40-45% long
term
- 81% of patients
who elect to keep
their device active
at 2-years.
Additional 25% of patients
(separate from the 42%),
improvement in symptoms of
25 -49%, which is short of
responder status
meaningful in the context of
severe, unremitting MDD?

50. 10 weeks
- Response rate 15%
- Remission rate 10%
12
months
- Response rate:
HAMD- 27% , CGI-I-
37%
- Remission rate 15%
24
months
- Response rate 42%
- Remission rate 22%
- Additional 25% of
patients with
inadequate (but
meaningful) response.

51. Manufacturer FDA
• One-year outcomes from its
pivotal trial.
One-year outcome:
• VNS+ TAU (n=205)vs TAU
(n=124) compared.
Adjunctive VNS
• Better outcomes compared to
TAU only.
• HAM-D the response rate with
VNS was 30% vs. 13% with TAU
• CGI-I the margin of superiority
was greater, 37% versus 12%
response rate.
• IDS-SR-30, the response rate
with VNS was 22% versus 12% for
TAU
Longer term, adjunctive
VNS:
• Increased response rate in TRD
by 2-3 fold,
• Fairly low absolute response
rates,
• Indicates impressive adjunctive
benefit from VNS in this severely
ill patient group

52.  The FDA approved the VNS implant for patients with
chronic or recurrent depression, (uni/bipolar) with a
history of failure of their depression to respond to at
least 4 antidepressant interventions.
 ECT failure is not a requirement to be eligible for VNS

54.  Indication
 TRD patients with bipolar and unipolar depressive
episodes as a long term adjunctive treatment option
 Failure to respond to ECT is not a prerequisite for VNS
eligibility,
 It may be appropriate to use ECT as an acute treatment
for severe depression to be followed by VNS as a long
term maintenance intervention.

55. Relative
Contraindications
 Not approved for psychotic
MDD or the depressed
phase of SAD.
 Paranoid ideation
 Unstable axis II disorders
 Borderline personality
disorder or other
disorders,
 Not studied in pregnancy-
 non-systemic treatment
 potential effects on fetus should
be limited
 Limitations in post-surgery MRI
 MRIs spine/joints prohibited.
 MRI brain possible w/ special
send-receive coils. (otherwise a CT scan
would need to substitute for an MRI)
 Dissatisfied?
 Could be switched off (the implant left
in place)
 Pulse generator could be
explanted.
 The electrode is left in situ--
adhesions around the vagus nerve
itself might increase risk of injury
during removal .
 Precautions with MRI remain in
place indefinitely
Special Precautions

56.  Dosing
 4 principal settings
1. current charge (mA),
2. pulse width (microseconds),
3. frequency (Hz),
4. duty cycle (on time relative to off time - in seconds and
expressed as a percentage).
 Start at 0.25 mA,  increase gradually in 0.25 mA increments
until a comfortable tolerance level is reached.
 Maximum tolerable level has been exceeded  pain/ bouts
of coughing.
 The stimulating device is then reset to the highest
‘comfortable’ setting.

57. Surgery
post 2 wks
•0.25 mA titrations in
current so that a
target dose of 1.0 mA
might be achieved at
the end of the first
month.
Weekly for
1 month
Q 2weeks for
1 month
Month 3
•Monthly visits if effective
•amplitude 1.0-1.5 mA range
and no improvement 
increase the duty cycle at
the juncture by adjusting
the on-off schedule.
Significant proportion of
responders to VNS only
emerge in the second 6
months of stimulation and
a full VNS trial may require
at least 12 months

59. safety
Surgery
SE to
Stimulation
Ψ Adverse
events

60. (Hypo)Mania
Depression
and
Suicidality
SI/SA Cognitive SE

61.  VNS device can remain functioning for up to 8 years.
 Patients are unable to adjust the treatment settings
independently.
 In the one year pivotal study (Rush et al. 2005)
 Continuation rate at 1 year was 90%.
 3% discontinued secondary to adverse events
 implant related infection,
 hoarseness,
 lightheadedness,
 postoperative pain
 chest and arm pain.
 7% -- lack of efficacy or other reasons.
 At 2 years (Nahas et al 2005)
 >80% of patients had device in place and functioning
 Most subjects electing to discontinue VNS because of lack of efficacy
rather than side effects.

62.  Safe and effective treatment in TRD
 FDA approved.
 Better results when used long term (12
weeks-1 year)
 Better results when combined with
meds. (can be combined with any meds
including MAOIs).
 Safe with ECT but it needs to be turned
off.
 No cognitive side effects.
 Can be used both for unipolar and
bipolar depression
 Dosing can be done in an outpatient
setting.
 Cautions
 Surgical risks
 Current and future MRI safety
 Side effects
http://www.utsouthwestern.edu/newsroom/news-releases/year-2005/vns-therapy-
for-treatment-resistant-depression-proves-effective-for-some-patients.html
Vagal Nerve Stimulation for Seizures. Textbook of Stereotactic and Functional
Neurosurgery. pp 2801-2822

63.  Safe and efficient neuromodulation modality in TRD.
 Over the longer term at one and at two years the
results observed with VNS appear reasonable in terms
of realistic expectations for this population.
 A controlled post marketing study as suggested by the
FDA is being conducted by the device manufacturer.
 Significant promise to treat TRD as a long term
treatment.

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65. altinam@ccf.org